Septic shock is a highly lethal condition. Early recognition of tissue hypoperfusion and its reversionare key factors for limiting progression to multiple organ dysfunction and death. Lactate‐targeted resuscitation is the gold‐standard under current guidelines, although it has several pitfalls including that non‐hypoxic sources of lactate might predominate in an unknown proportion of patients. Peripheral perfusion‐targeted resuscitation might provide a real‐time response to increases in ow that could lead to a more timely decision to stop resuscitation, thus avoiding uid overload and the risks of over‐resuscitation. This article reports the rationale, study design and analysis plan of the ANDROMEDA‐SHOCK Study.Methods: ANDROMEDA‐SHOCK is a randomized controlled trial which aims to determine if a peripheral perfusion‐ targeted resuscitation is associated with lower 28‐day mortality compared to a lactate‐targeted resuscitation in patients with septic shock with less than 4 h of diagnosis. Both groups will be treated with the same sequential approach during the 8‐hour study period pursuing normalization of capillary re ll time versus normalization or a decrease of more than 20% of lactate every 2 h. The common protocol starts with uid responsiveness assessment and uid loading in responders, followed by a vasopressor and an inodilator test if necessary. The primary outcomeis 28‐day mortality, and the secondary outcomes are: free days of mechanical ventilation, renal replacement therapy and vasopressor support during the rst 28 days after randomization; multiple organ dysfunction during the rst 72 h after randomization; intensive care unit and hospital lengths of stay; and all‐cause mortality at 90‐day. A sample size of 422 patients was calculated to detect a 15% absolute reduction in mortality in the peripheral perfusion group with 90% power and two‐tailed type I error of 5%. All analysis will follow the intention‐to‐treat principle.Conclusions: If peripheral perfusion‐targeted resuscitation improves 28‐day mortality, this could lead to simpli ed algorithms, assessing almost in real‐time the reperfusion process, and pursuing more physiologically sound objec‐ tives. At the end, it might prevent the risk of over‐resuscitation and lead to a better utilization of intensive care unit resources.